Generating a Systemic Immune Response Using Localized Delivery of Chemotherapy in Brain Tumors

使用脑肿瘤局部化疗产生全身免疫反应

• 批准号: 10328420
• 负责人: Michael Lim
• 金额: $ 37.42万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10328420
• 关键词: Generating; Systemic; Immune; Response; Using

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and is associated with a dismal prognosis. Immunotherapy has demonstrated potential to generate durable antitumor activity in other types of cancer. In particular, agents that selectively target checkpoint molecules, such as anti-CTLA-4 and anti-PD-1 antibodies, have accelerated the field of cancer immunotherapy by directly combating the tumor's mechanisms of immune evasion. Notable results with these agents have already been reported in advanced melanoma, renal cell carcinoma, and lung cancer and trials are underway in GBM. Chemotherapy, which is part of the standard of care for patients with GBM, has been associated with immunosuppressive effects and with myeloablative results. Recent data from our laboratory shows that local chemotherapy may be a better alternative to systemic chemotherapy given that it avoids these untoward effects. The main goal of this proposal is to understand the main mechanisms by which GBM evades the immune system and how to thwart these mechanisms with local chemotherapy and checkpoint blockade to enhance an effective immune response against GBM. Our data demonstrates that local chemotherapy in combination with anti-PD-1 increases survival and provides an increase in memory T cells in an orthotopic glioma model and protects against tumor re-challenge. We propose to study: 1. Potential biomarkers of response in patients with GBM treated with LC and anti-PD-1 therapy as part of an ongoing clinical trial at our institution. 2. The neoantigen profile generated by LC in intracranial chemosensitive and chemoresistant murine gliomas, to determine the impact on TCR diversity and anti-tumor immune response. 3. The location and identity of APCs responsible for antigen presentation induced by LC. These data will have direct clinical relevance for the findings and can be translational into clinical trials and patient care. We expect that the data generated from these studies will provide novel insights into a previously unexplored aspect of chemotherapy and serve as a foundation for optimizing the efficacy of therapy and host immune function against GBM. The knowledge obtained from this study will undoubtedly result in better therapeutic alternatives for current unsuccessful treatment for patients with GBM.

胶质母细胞瘤（GBM）是成人中最常见的原发性恶性脑肿瘤， 预后不佳免疫疗法已被证明有可能在其他癌症中产生持久的抗肿瘤活性。 癌症的类型。特别地，可以使用选择性靶向检查点分子的试剂，例如抗CTLA-4和 抗PD-1抗体，通过直接对抗肿瘤的免疫反应，加速了癌症免疫治疗领域的发展。 免疫逃避机制。这些药物的显著效果已经提前报道 黑色素瘤、肾细胞癌和肺癌，并且正在GBM中进行试验。化疗， 作为GBM患者标准治疗的一部分，与免疫抑制作用相关， 清髓性结果我们实验室的最新数据显示，局部化疗可能是一种更好的治疗方法。 这是全身化疗的替代方案，因为它避免了这些不良反应。这个的主要目标 一个建议是了解GBM逃避免疫系统的主要机制，以及如何阻止GBM的免疫系统。 这些机制与局部化疗和检查点封锁，以提高有效的免疫 对GBM的反应。我们的数据表明，局部化疗联合抗PD-1 在原位神经胶质瘤模型中增加存活并提供记忆T细胞的增加， 对抗肿瘤再攻击。我们建议研究：1。GBM患者中缓解的潜在生物标志物 作为我们机构正在进行的临床试验的一部分，接受LC和抗PD-1治疗。2.新抗原 在颅内化学敏感和化学耐药的小鼠胶质瘤中通过LC产生的谱，以确定 影响TCR多样性和抗肿瘤免疫应答。3.负责运输的装甲运兵车的位置和身份 LC诱导的抗原提呈。这些数据将与研究结果直接相关， 转化为临床试验和病人护理。我们预计，这些研究产生的数据将 为以前未探索的化疗方面提供了新的见解，并作为基础， 优化针对GBM的治疗功效和宿主免疫功能。由此获得的知识 这项研究无疑将为目前不成功的患者提供更好的治疗方案 关于GBM